Abstract 1345: p300/CBP bromodomain inhibitor CCS1477 enhances the efficacy of immune checkpoint blockade therapy in cancer treatment
Authors: Jinghui Liu, Xinyi Wang, Katelyn Jones, Nigel Brooks, Neil Pegg, Xiaoqi Liu
Journal: Cancer Research (2022)

Abstract Background: Blockade of programmed death-ligand 1 (PD-L1) by therapeutic antibodies has shown to be a promising strategy in cancer therapy, yet clinical response in many types of cancer is limited. Tumor cells secrete PD-L1 through exosomes or splice variants, which has been described as a new mechanism for the resistance to PD-L1 blockade therapy in multiple cancers. Our previous findings showed that the histone acetyltransferases p300/CBP could be recruited to the promoter of CD274 (encoding PD-L1) to regulate the expression of PD-L1. P300/CBP inhibition abrogated this process and reduced the secretion of exosomal PD-L1 by blocking the transcription of CD274, which combined with the anti-PD-L1 antibody to reactivate T cells function for tumor attack. In this study we have tested the outcome of combined immune checkpoint inhibitors with CCS1477, a novel p300/CBP bromodomain inhibitor, in pre-clinical models of prostate cancer and melanoma. Results: CCS1477 significantly decreased human prostate (DU145/PC-3) and melanoma (A375/SK-MEL-28) cancer cell line PD-L1 expression, as well as exosome secreted PD-L1 after 24 hours treatment. Moreover, consistent with these findings in vitro, CCS1477 (2.5mg//kg) also reduced PD-L1 expression in a syngeneic mouse prostate model (TRAMP-C2) and syngeneic mouse melanoma model (B16-F10). Meanwhile, CCS1477 treatment significantly increased tumor-infiltrating CD8+ and CD4+ T cells in syngeneic mouse models. Monotherapy treatment with CCS1477 or immune checkpoint inhibitors (anti-PD-L1 antibody for prostate cancer or anti-PD-L1 and anti-CTLA4 antibody for melanoma) resulted in significant but modest efficacy. Strikingly, the combination of immune checkpoint inhibitors with CCS1477 showed robust synergistic responses resulting in tumor regression. Mechanistically, CCS1477 treatment induced significant loss of H3K27 acetylation from super-enhancers of CD274, which subsequently induced a significant reduction of PD-L1 expression and exosome secreted-PD-L1. Also, we found that CCS1477 treatment significantly decreased the abundance of circulating and tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which are known to play important roles in tumor immune evasion by inhibiting T cell’s activation. Reduction of MDSCs and exosome secreted-PD-L1 preserved T-cell function and elicited robust immunotherapy response combined with immune checkpoint blockade agents. Conclusions: These observations illuminate a clinically relevant hypothesis for combining CCS1477 with immune checkpoint blockade in the treatment of cancer. Citation Format: Jinghui Liu, Xinyi Wang, Katelyn Jones, Nigel Brooks, Neil Pegg, Xiaoqi Liu. p300/CBP bromodomain inhibitor CCS1477 enhances the efficacy of immune checkpoint blockade therapy in cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1345.